P307: DEL(17)(Q11) IS TYPICAL MARKER OF IMMATURE T-ALL OF ADULTS, WITH NF1, UTP6, AND SUZ12 HAPLOINSUFFICIENCY, GENOME INSTABILITY, AND GENE DOWNREGULATION
Authors: V. Bardelli, V. Pierini, S. Arniani, E. Mvridou, C. Matteucci, A. G. Lema Fernandez, M. Moretti, L. Elia, F. Giglio, F. Forghieri, M. Cerrano, N. Fracchiolla, M. Delia, S. Sica, C. Mecucci, R. La Starza
Journal: HemaSphere (2022)

Background: T-ALLs derive from the accumulation of multiple genetic and epigenetic events. Some deregulate T-cell transcription factors and define specific genetic subtypes, while the large majority are involved in pivotal cellular processes, such as signaling, cell cycle, apoptosis, proliferation, ribosome biogenesis, and epigenetic modulation. Genomic imbalances, and in particular deletions, are the most frequent cytogenetic rearrangements in T-ALL. Whether cryptic or large, they often share loss regions - the common deletion region (CDR) - where they map putative suppressor genes that undergo haploinsufficiency or inactivation, thus driving the leukemogenic process. Aims: Our study focused on T-ALL cases harboring interstitial del (17q) with the aim of assessing the incidence and distribution of this cytogenetic marker, and to detect associated clinical and molecular features. Methods: The study was carried out on 378 adult (=223) and pediatric (=155) T-ALL, including 279 males and 99 females. The genetic background was investigated by integrated molecular-cytogenetics (FISH and SNPa),1 RNA microarrays (Affymetrix), targeted sequencing (custom card by Sophia Genetics, Arrow Diagnostics), and RTq-PCR. Data analysis was carried out referring to available databases (UCSC, NCBI, Data of Genomic Variants, Biocarta, KEGG, Reactome). Results: Cases were classified according to genetic rearrangements as HOXA (=104), TAL/LMO (=74), TLX1/NKX2.1 (=50), TLX3 (=42), BCL11B-a (=8), SPI.1 (=2); 98 were undetermined. Interstitial monoallelic del(17q) was detected 31/378 cases and was mainly found in cases with HOXA related abnormalities (8/104) or cases undetermined (17/98). There were 27 adults and 4 children (p<0.0001). In 19/24 with available flow cytometry the diagnosis was consistent with ETP/near ETP ALL (p<0.001). All cases shared a common deleted region (CDR) of about 650kb, that invariably involved SUZ12, UTP6, and NF1 which were expressed at a significantly lower level than in T-ALL without del(17q). RNA microarray showed that 148 differentially expressed genes (DEG), 67 up- and 81 down- regulated, distinguished del(17q) T-ALL cases from T-ALL without. Among up-regulated there were MEF2C, MN1, and IGFBP7, which have been all associated with an immature phenotype, and MAF and RUNX2 transcription factors. Instead, among down-regulated, there were putative suppressors involved in genome stability, i.e. BRCA1, FANCI, BRIP1, XRCC2, and CHEK1. Accordingly, cell cycle, homologous recombination, DNA replication, and Fanconi anemia pathways, were significantly deregulated in T-ALL with del(17q), and a significant association with deletions of RB1 (37%)(p<0.001) and TP53 (20%)(p=0.017) emerged. In addition, del(17q) cases had a higher number (≥5) of copy number abnormalities (p<0.001). Other recurrent alterations affected JAK/STAT members and/or modulators (56% of cases). Summary/Conclusion: Del(17q) was a recurrent marker in immature T-ALL of adults and characterized 19% of cases undetermined at molecular-cytogenetic level. It caused the monoallelic loss/haploinsufficiency of three genes, i.e. NF1, UTP6, and SUZ12, that restricted the CDR. Our study provided evidence that del(17q) identified a major leukemogenic mechanism, through the cooperation of: 17q genes loss of function, JAK/STAT constitutive activation, and altered cell cycle. Interestingly, RUNX2 and IGFBP7, high-risk markers in T-ALL,2,3 were aberrantly expressed in this subset of T-ALL. 1La Starza R, et al. J Mol Diagn 2020 2Matthijssens F, et al. JCI 2021 3Bartram I, et. al., BMC Cancer 2015